Synthesis and biological evaluation of novel quinazoline-derived human Pin1 inhibitors

A series of novel 2,4-disubstituted quinazoline derivatives were prepared and their inhibitory activities on hPin1 were evaluated. Of all the synthesized compounds, eight compounds displayed inhibitory activities with IC(50) value at the level of 10(-6)mol/L. Preliminary structure-activity relationships were analyzed in details and the binding mode of the titled compounds was predicted using FlexX algorithm. The design and optimization of novel small molecule Pin1 inhibitors will be guided by the results of this report.     

Aminostyrylbenzofuran derivatives as potent inhibitors for Abeta fibril formation

The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Abeta fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Abeta fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC(50)=0.07 and 0.08 microM, respectively) than those of Curcumin (IC(50)=0.80 microM) and IMSB (IC(50)=8.00 microM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.     

Synthesis and acrosin inhibitory activities of substituted ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives

A series of novel ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives were designed and synthesized and their in vitro acrosin inhibitory activities were evaluated. Most of the compounds exhibited acrosin inhibitory activities. Among them, three compounds (5l, 5n, and 5v) were more potent than that of the control TLCK. These provide a new structural type for the development of novel contraceptive acrosin inhibitory agents.     

Synthesis and acrosin inhibitory activity of methyl 5-substituted-1H-benzo[d]imidazol-2-yl carbamate derivatives

A series of novel methyl 5-substituted 1H-benzo[d]imidazol-2-ylcarbamates were designed, synthesized, and their acrosin inhibitory activities evaluated in vitro. The results of acrosin inhibitory activity showed that all title compounds were more potent than the control TLCK. Compound 4w displayed the most potent acrosin inhibitory activity among all the compounds, with an IC(50) of 6.3×10(-5)M. The studies provide a new structural class for the development of novel acrosin inhibitory agents.     

Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979).     

Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling

A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.     

Design, synthesis and biological activities of thiourea containing sorafenib analogs as antitumor agents

A novel series of diaryl thiourea containing sorafenib derivatives 9a-t was designed and synthesized. The structures of all the newly synthesized compounds were determined by (1)H NMR, (13)C NMR and HRMS. Their antiproliferative activities against HCT116 and MDA-MB-231 cell lines, and their inhibitory activities against the phosphorylation of VEGFR were evaluated and described. Some of the compounds showed significant activities against both cell lines and VEGFR. Compounds 9g, 9m, 9o and 9p demonstrated competitive antiproliferative activities to sorafenib, the reference standard, while compounds 9d, 9m, and 9p showed significant inhibitory activities against the phosphorylation of VEGFR.     

Design, synthesis and antitumor activity of 4-aminoquinazoline derivatives targeting VEGFR-2 tyrosine kinase

We report herein the design and synthesis of novel 4-aminoquinazoline derivatives based on the inhibitors of VEGFR-2 tyrosine kinases. The VEGFR-2 inhibitory activities of these newly synthesized compounds were also evaluated and compared with that of ZD6474. We found that most of target compounds had good inhibitory potency. In particular, compounds 1h, 1n and 1o were found to be 6, 2 and 2-fold more potent than the positive control ZD6474. The leading compound 1h also showed an in vivo activity against HepG2 human tumor xenograft model in BALB/c-nu mice.     

Design,synthesis and biological evaluation of novel aryl-acrylic derivatives as novel indoleamine-2,3-dioxygenase 1 (IDO1) inhibitors

Two series of novel aryl-acrylic derivatives were designed, synthesized, and screened in enzymatic and cellular inhibitory activities. All compounds showed moderate to significant potency. The SAR analyses indicated that the semicarbazone linker is better than the 1,2,3-triazole linker. Among semicarbazone compounds that R₁ bearing di-chain amino groups exhibited superior activities to those with morpholino group. Furthermore, compounds with electron-withdrawing groups at the 2-position or 4-position on the terminal phenyl ring were more active. Among these, compounds 7g, 7i, 7m and 7n exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against normal HeLa cells. In addition, the study suggested that the aryl-acrylic is an interesting novel scaffold for IDO1 inhibition for further development.     

Design, synthesis, and in vitro antiproliferative activity of novel Dasatinib derivatives

Two series of novel Dasatinib derivatives have been designed and synthesized, with their in vitro cytostatic effect screened on human chronic myeloid leukemia cell line K562 and human myeloid leukemia cell line U937. Some target compounds demonstrated significant inhibitory activities against both cell lines. Compared to the contrast drug Dasatinib, 1b, 1c, 1d, 1e and 1f were found to demonstrate more potent antitumor activities. The structures of all the newly synthesized compounds were determined by (1)H NMR and (13)C NMR.     

5-lipoxygenase inhibitors with histamine H(1) receptor antagonist activity

A series of novel compounds with both 5-lipoxygenase (5-LO) inhibitory and histamine H(1) receptor antagonist activity were designed for the treatment of asthma. These dual-function compounds were made by connecting 5-LO and H(1) pharmacophores,N-hydroxyureas and benzhydryl piperazines, respectively. A range of in vitro activities was observed, with the furan analog 10 demonstrating both activities in an animal model. The activities observed were compared to single-function drugs.     

Investigation of antioxidant properties of some 6-(alpha-aminobenzyl)thiazolo[3,2-b]-1,2,4-triazole-5-ol compounds

Promising antiinflammatory activity together with low ulcerogenic properties of some Michael addition products of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones which have been synthesized in our previous study, prompted us to investigate their antioxidant properties. Since compound Ib has both antioxidant and antiinflammatory activities beside the lowest ulcerogenic incidence, it was selected for investigation of its inhibitory effect on various cyclooxygenase ezymes. It was found that while it did not inhibit cyclooxygenase-1 (COX-1) enzyme, there was a small inhibitory effect (17%) on COX-2 enzyme. We concluded that the diminished harmful effects on the stomach of this novel antiinflammatory compound were related to its antioxidant properties since it is ineffective on COX-1 enzyme. In conclusion, the compounds having both antioxidant and antiinflammatory activities with a lack of COX-1 enzyme inhibitory effect may improve the gastrointestinal safety profile of such compounds.     

Synthesis,structural studies,and biological evaluation of some purine substituted 1-aminocyclopropane-1-carboxylic acids and 1-amino-1-hydroxymethylcyclopropanes

The novel purine derivatives of 1-aminocyclopropane-1-carboxylic acid (8 and 9) and 1-amino-1-hydroxymethylcyclopropane (12 and 13) with methylene spacer between the base and the cyclopropane ring were prepared by multistep synthetic route involving alkylation of adenine and 6-(N-pyrrolyl)purine with 2-hydroxy-methyl-1-aminocyclopropane-1-carboxylic acid derivative 3 as a key reaction. All novel compounds were racemic. The N-9 substitution of the purine ring and the Z-configuration of the cyclopropane ring in 4-13 were deduced from their 1H and 13C NMR spectra by analyses of chemical shifts, H-H coupling constants and connectivities in two-dimensional homo- and heteronuclear correlation spectra. An unequivocal proof of the stereostructure of 1, 4 and 5 was obtained by their X-ray structure analysis. The novel compounds were evaluated on cytostatic and antiviral activities in several cell lines. The 6-(N-pyrrolyl)purine derivative of 1,2-aminocyclopropane alcohol 12 exhibited a more pronounced inhibitory activity against the proliferation of cervical carcinoma (HeLa) and human fibroblast (WI-38) cells than other types of tumor cell lines. None of the compounds showed inhibitory activities against cytomegalovirus, varicella-zoster virus or other viruses.     

Synthesis and biological evaluation of N-aryl salicylamides with a hydroxamic acid moiety at 5-position as novel HDAC-EGFR dual inhibitors

A novel series of N-aryl salicylamides with a hydroxamic acid moiety at 5-position were synthesized efficiently. Their activities against EGFR kinase and HDACs were evaluated. All compounds displayed inhibitory activity against EGFR and HDACs. The antiproliferative activities of synthesized compounds were evaluated by MTT method against human cancer cell lines A431, A549 and HL-60. Compound 1o showed the most potent inhibitory activity against A431 and A549. Compounds 1k and 1n exhibited higher potency against HL-60 than gefitinib and SAHA. N-Aryl salicylamides with a hydroxamic acid moiety at 5-position is another new HDAC-EGFR dual inhibitors.     

Design, synthesis and biological evaluation of β-carboline derivatives as novel inhibitors targeting B-Raf kinase

β-Carboline family of compounds is a large group of alkaloids widely distributed in nature and exhibits broad-spectrum anti-tumor activities. We designed and synthesized two series of novel 1-carboxamide- and 6-sulfonamide-substituted β-carboline derivatives 7a-p and 12a-b, and their wild type B-Raf kinase inhibitory activities were described. Most compounds showed moderate to excellent inhibitory activities. Among them, 1-carboxamide-6-(N-(3-(dimethylamino)propyl)-sulfamoyl)-β-carboline, 7e exhibited potent activity (IC(50)=1.62 μM), showing the potential for further investigation as a lead compound.     

Synthesis and biological activities of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives as PDE4 inhibitors

A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.     

萘查耳酮类化合物的设计合成及对CYP1B1酶的抑制活性评价

目的:设计并合成几类新型的萘查耳酮衍生物,初步测定其对CYP1B1酶的抑制活性,筛选具有良好抗癌作用的CYP1B1抑制剂。方法:以1,5-二羟基萘为原料,首先合成两个重要的中间体2-乙酰基-1,4,5,8-四甲氧基萘、1,5,6-三甲氧基-2-萘乙酮,然后利用羟醛缩合反应合成所需要的化合物。结果:合成了19个目标化合物,其结构均经过核磁共振氢谱确证,所有化合物均为全新化合物。对所合成的新化合物均进行了EROD酶实验测定。结论:所合成的化合物均具有较强的CYP1B1酶一抑制活性,其中4-1、4-2、5'-1对CYP1B1的抑制活性强于CYP1B1强抑制剂α-萘黄酮(IC50=11 nmol/L),他们的IC50分别为6.5、0.47、8nmol/L。     

Investigation of antioxidant properties of some 6-(α-aminobenzyl)thiazolo[3,2-b]-1,2,4-triazole-5-ol compounds

Promising antiinflammatory activity together with low ulcerogenic properties of some Michael addition products of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-ones which have been synthesized in our previous study, prompted us to investigate their antioxidant properties. Since compound Ib has both antioxidant and antiinflammatory activities beside the lowest ulcerogenic incidence, it was selected for investigation of its inhibitory effect on various cyclooxygenase ezymes. It was found that while it did not inhibit cyclooxygenase-1 (COX-1) enzyme, there was a small inhibitory effect (17%) on COX-2 enzyme. We concluded that the diminished harmful effects on the stomach of this novel antiinflammatory compound were related to its antioxidant properties since it is ineffective on COX-1 enzyme. In conclusion, the compounds having both antioxidant and antiinflammatory activities with a lack of COX-1 enzyme inhibitory effect may improve the gastrointestinal safety profile of such compounds.     

Azabicyclic sulfonamides as potent 11β-HSD1 inhibitors

Inhibition of 11β-HSD1 has demonstrated potential in the treatment of various components of metabolic syndrome. We wish to report herein the discovery of novel azabicyclic sulfonamide based 11β-HSD1 inhibitors. Highly potent compounds exhibiting inhibitory activities at both human and mouse 11β-HSD1 were identified. Several compounds demonstrated significant in vivo activity in the mouse cortisone challenge assay.     

Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors

Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated. Among these compounds, compounds 5a and 5e exhibited high cytotoxicity against HepG-2 cells with IC?? values at ～2 μM. Further kinase assay study showed that compound 5a have good EGFR inhibitory activity and moderate VEGFR-2 and PDGFR inhibitory activities, while 5e have moderate EGFR inhibitory activity and slightly weaker VEGFR-2 and PDGFR inhibitory activities. Molecular docking analysis suggested that compound 5a more tightly interacts with EGFR and PDGFR than compound 5e. Our study discovered a novel series of benzimidazole derivatives as multi-target EGFR, VEGFR-2 and PDGFR kinases inhibitors.